This application is in response to PA-07-079, Research on the Reduction and Prevention of Suicidality and is a competing continuation of R01MH 61017, Treating Suicidal Behavior and Self-Mutilation in BPD. Suicidal behavior non-suicidal self-injurious behavior and depression are key problems in borderline personality disorder (BPD). Up to 10% of individuals affected with this disorder die by suicide, however, development of effective treatments for suicidal behavior and self-injury and understanding of mechanisms of action of treatment has received little attention. This project is a continuation of a randomized clinical trial of fluoxetine and Dialectical Behavior Therapy (DBT) for the treatment of suicidal behavior and non-suicidal self injury (NSSI). We achieved a nearly 80% reduction in suicide attempt rate comparing the treatment year to the year prior to study entry. DBT and fluoxetine have specific efficacy in achieving overall improvement at six months relative to supportive therapy and placebo. While at 12 months the differences in overall improvement are no longer present, the speed of response is important due to the seriousness of the problems being treated. Also, NSSI was significantly reduced in those with substance use disorders with DBT and fluoxetine. Furthermore, suicide attempts in the DBT condition were half the number of the supportive therapy condition. Fluoxetine at a high dose was associated with suicide attempts, thus, while helpful in overall improvement and NSSI, fluoxetine should be maintained at lower doses in order to avoid suicidal behavior. We now know, based on recent research from others in our group that almost complete serotonin receptor blockade is achieved at relatively low doses and, therefore, higher doses are likely to affect other systems and be responsible for side effects without additional therapeutic benefit. In our continuation, we plan to build on our current findings by comparing DBT to a strategy frequently used in clinical practice, clinical management with fluoxetine at lower dosage (no more than 40mg) with the option of switching to another SSRI. The project also uses translational neuroscience measures, neuropsychological testing, biobehavioral measures and fMRI at baseline and at the end of treatment, to evaluate emotion regulation and impulsivity, two key components of BPD, as moderators and predictors of treatment change. Furthermore, our preliminary data demonstrates that a 6-month treatment may be as effective in treating these behaviors and we plan to test this model. The findings of the proposed study will help to provide an accessible and rational treatment strategy for suicidal and self injuring individuals with BPD. This project is innovative in that: it is the first trial to compare DBT to a standard medication strategy; it uses a well-justified six month model instead of 12 months; it incorporates both biobehavioral and imaging measures at baseline and end of treatment to evaluate predictors and moderators of change; it addresses suicide-related outcomes and the risk of risk of antidepressant emergent suicidality. Suicide, suicide attempts and depression occur at a high rate in borderline personality disorder. The findings of the proposed study will help to provide an accessible and rational treatment strategy for suicidal and self injuring individuals and will also provide information on differential efficacy and mechanisms of action for these treatments.